Cellular immortality is a near-universal phenotype of cancer cells with the central role played by the multicomponent telomerase complex firmly established. The reactivation of telomerase is found in approximately 85% of all cancers. Furthermore, frequent activating non-coding mutations in the hTERT promoter region have been identified in multiple tumour types. A considerable body of evidence supports the concept of targeting the signal transduction pathways that contribute to telomerase overexpression in cancer cells. We have exploited our knowledge in this area to develop cell-based luciferase reporter gene assays to measure hTERT and hTR gene promoter activity. To this end we undertook high throughput screening in the A2780 human ovarian cancer cell line against both hTR and hTERT promoters. Secondary specificity and cytotoxicity assays reduced the initial hits to a single chemical series of dual inhibitors which strongly suppress both hTR and hTERT promoter activity without primary cytotoxicity, as predicted of telomerase inhibitors. Through a process of Hit to Lead we have further developed the chemical series. Lead compounds are active across a panel of cell lines from distinct histological origins, reduce endogenous hTERT mRNA levels and decrease telomerase catalytic activity at nM concentrations. Furthermore, these compounds repress both wild type and mutant C228T and C250T hTERT promoter activity. In specificity assays no off-target activity has been identified in an expanded promoter screen against a panel of 15 offtarget promoter reporters.

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